Topical antifungal compositions and methods of use thereof

ABSTRACT

Described herein are topical anti-fungal pastes and methods that treat fungal infections of the skin, reduce the severity and duration of symptoms of fungal infections of the skin, and prevent recurrence of fungal infections. The topical pastes described herein are composed of an admixture of one or more antifungal agents, excipient inert powder, and a pharmaceutically acceptable topical carrier. The compositions and methods described herein minimize fungal resistance and maximize the number of targeted fungal strains. Additionally, the compounds and methods do not suppress the body&#39;s immune system either locally or systemically, thus allowing for a faster restoration of normal skin flora. The compositions and methods described herein are particularly suitable for use in infants and children as well as in immunocompromised individuals, diabetics, and the obese.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 USC 371 application of internationalapplication number PCT/US2014/ 59228, filed on Oct. 4, 2016, which is acontinuation-in-part of U.S. Nonprovisional patent application Ser. No.14/050,094, filed on Oct. 9, 2013. All applications are herebyincorporated herein by reference in their entireties.

BACKGROUND

The superficial layers of the skins and mucous membranes of humans andother animals play host to a variety of microorganisms, includingnumerous species of fungi and bacteria. Balance between skin flora andthe host organisms is normally maintained at a steady level, butuncontrolled fungal growth occurs regularly in the obese, in diabetics,and in immunocompromised individuals such as cancer patients undergoingchemotherapy, HIV positive persons, and transplant recipients takinganti-rejection drugs, among others.

Candida albicans occurs naturally on the body, particularly in warm,moist areas. Intertrigo is an overgrowth of Candida yeast in areas suchas the groin, armpits, between the buttocks, under heavy breasts, theinner thighs, the perianal area, the genital area, between the toes, thecrease of the neck, between abdominal fat folds, and other bodysurfaces. Intertrigo also presents as diaper rash. Overgrowth of yeastssuch as Candida is particularly problematic in institutional settings;prevalence ranges from 6% of hospital patients to 17% of those residingin nursing homes. Up to 20% of home-bound patients also experiencetopical yeast imbalances. Any persons experiencing restricted mobilitymay be at increased risk for intertrigo. Other contributing factorsinclude incontinence, heat, humid weather, tight clothing, lack of aircirculation, friction between skin folds, excessive sweating, poorhygiene, malnutrition, inflammatory skin conditions such as psoriasis,and the use of topical steroids.

Candidal diaper dermatitis (diaper rash) is a common yeast overgrowthinfection caused by C. albicans that frequently presents in the perianalarea and between the buttocks of infants and toddlers. Visits tooutpatient pediatric offices for diaper rash total one million per yearin the United States. The skin of infants is thinner than that of adultsand produces fewer secretions. Thus, infant skin is more susceptible toirritation and infection. Measures such as frequent diaper changes,avoidance of moisture-impervious diaper covers, and leaving children forlong periods of time without diapers can help prevent diaper rash.However, topical antifungal therapy is still necessary for theresolution of candidal diaper rash.

Symptoms of Candida imbalance include redness, irritation, intenseitching, burning, pain, and odor. Physicians often prescribe combinationsteroid/antifungal creams such as Mycolog (mystatin/triamcinolone),Lotrisone (clotrimazole/betamethasone), or Vytone(iodoquinol/hydrocortisone), to intertrigo patients. While these rapidlyrelieve symptoms, fungal resurgence after corticosteroid treatment iscommon. These recurrences of symptoms often exceed the initialpresentation. Although triamcinolone, betamethasone, and hydrocortisoneprovide immediate relief of symptoms, they also suppress the body's ownimmune response in the inflamed and/or macerated areas. Thus, a needexists for a non-steroidal treatment for Candida overgrowth andintertrigo.

SUMMARY

Described herein are topical anti-fungal pastes and methods that treatfungal infections of the skin, reduce the severity and duration ofsymptoms of fungal infections of the skin, and prevent recurrence offungal infections. The topical pastes described herein are composed ofan admixture of one or more antifungal agents, excipient inert powder,and a pharmaceutically acceptable topical carrier. The compositions andmethods described herein minimize fungal resistance and maximize thenumber of targeted fungal strains. Additionally, the compounds andmethods do not suppress the body's immune system either locally orsystemically, thus allowing for a faster restoration of normal skinflora. The compositions and methods described herein are particularlysuitable for use in infants and children as well as in immunocompromisedindividuals, diabetics, and the obese.

The advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the aspects describedbelow. The advantages described below will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive.

DETAILED DESCRIPTION

Before the present compounds, compositions, and/or methods are disclosedand described, it is to be understood that the aspects described beloware not limited to specific compounds, synthetic methods, or uses assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an imidazole antifungal” includes mixtures of two or moresuch antifungal, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not. For example, the phrase “optionally includes an excipientinert powder” means that the inert powder can or cannot be included inthe composition and that the description includes compositions where thepowder is included and compositions where it is not included.

References in the specification and concluding claims to parts byweight, of a particular element or component in a composition orarticle, denotes the weight relationship between the element orcomponent and any other elements or components in the composition orarticle for which a part by weight is expressed. Thus, in a compoundcontaining 2 parts by weight of component X and 5 parts by weightcomponent Y, X and Y are present at a weight ratio of 2:5, and arepresent in such ratio regardless of whether additional components arecontained in the compound.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

By “subject” is meant an individual. The subject can be a mammal such asa primate or a human. The term “subject” can include domesticatedanimals including, but not limited to, cats, dogs, etc., livestock(e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals(e.g., mouse, rabbit, rat, guinea pig, etc.).

By “contacting” is meant an instance of exposure by close physicalcontact of at least one substance to another substance. For example,contacting can include contacting a body surface, such as the skin of asubject, with a topical composition described herein.

“Treatment” or “treating” means to administer a composition to a subjector a system with an undesired condition (e.g., fungal infection) toreduce the symptoms of the undesired condition when compared to the samesubject that is not administered the composition. The compositionsdescribed herein can reduce or arrest (i.e., stop) fungal growth in asubject. The topical compositions described herein can be applieddirectly to the infected area on the subject and/or near the theninfected area.

In other aspects, the compositions described herein can prevent fungalgrowth in a subject. Here, the topical compositions described herein canbe applied to an area of the subject that is prone to fungal infection.

By “effective amount” is meant a therapeutic amount needed to achievethe desired result or results.

“Topical” refers to a composition that is applied to the surface of asubject's body. Topical compositions may be applied, for example, to theskin, mucous membranes, hair, nails, or any other exposed surface of thebody.

A “fungal infection” is the invasion of the body by pathogenic fungi.This invasion can produce tissue injury and/or discomfort for theinfected individual. Fungal infections can be opportunistic (e.g.,resulting front overgrowth of skin microbiota during conditions ofimmune suppression) or can be acquired from the environment (e.g.,nosocomial infections). An “antifungal” compound or composition isadministered to subjects having fungal infections to kill as well asreduce or prevent the growth of fungi.

“Burow's solution” is an aqueous solution of aluminum acetate used inpharmacological applications, which may range in concentration from 5%to 13%, depending on the desired use. Burow's solution is commonlyemployed for control of symptoms associated with inflammatory skinconditions and also is known to have antibacterial properties. It istraditionally applied in a cold compress but can optionally be used as acleanser or astringent.

An “excipient” is a pharmacologically inactive substance included in apharmaceutical composition. Excipients are used for a variety ofpurposes including binders and fillers, coatings, colors and flavors,preservatives, sweeteners, and the like, and are frequently employed toaid in the distribution and/or dispensing of pharmaceuticalpreparations. An “inert” excipient is an excipient that will not react,biologically or chemically, with the other components of the compositionof which it is a part.

“Powder” is composed of fine particles. Dry substances may be reduced topowders by techniques such as, for example, grinding, pounding, ortriturating.

I. Topical Pastes and Preparation Thereof

Described herein are topical pastes that reduce, arrest, or preventfungal growth in a subject. The topical pastes described herein arecomposed of an admixture of one or more antifungal agents, excipientinert powder, and a pharmaceutically acceptable topical carrier. Eachcomponent used to prepare the topical formulations described herein isdiscussed in detail below.

Antifungal Agents

The topical pastes described herein include one or more antifungalagents. In one aspect, the antifungal agent is an antifungal imidazole.An “antifungal imidazole” is a compound that possesses antifungalproperties and contains at least one imidazole ring substituent. Theimidazole ring can optionally be further substituted. Imidazoleantifungals can include, but are not limited to, clotrimazole,miconazole, ketoconazole, econazole, oxiconazole, luliconazole andcombinations thereof. Not wishing to be bound by theory, imidazoleantifungals mechanistically have been shown or proposed to inhibitbiosynthesis of the fungal sterol ergosterol, to interact with membranephospholipids, to inhibit endogenous respiration, and to inhibittransformation of yeasts to mycelial forms.

In another aspect, the antifungal agent is clotrimazole, ketoconazole,miconazole, oxiconazole, econazole, luliconazole, terbinafine, nystatin,fluconazole, voriconazole, itraconazole, caspofungin, micafungin,naftifine, butenafine, amorolfine, ravuconazole, posaconazole,flucytosine, sertaconazole, efinaconazole, enilaconazole, saperconazole,sulconazole, terconazole, tioconazole, nikkomycin Z, anidulafungin(LY303366), pimaricin, griseofulvin, ciclopirox, haloprogin, tolnaftate,undecylenate, or any combination thereof.

The topical pastes described herein can include a single antifungalagent or two or more antifungal agents described herein. In one aspect,the antifungal agent includes a first agent and second agent, whereinthe first agent is clotrimazole, ketoconazole, miconazole, oxiconazole,econazole, luliconazole, terbinafine, fluconazole, voriconazole,itraconazole, caspofungin, micafungin, naftifine, butenafine,amorolfine, ravuconazole, posaconazole, flucytosine sertaconazole,efinaconazole, enilaconazole, saperconazole, sulconazole, terconazole,tioconazole, nikkomycin Z, anidulafungin (LY303366), pimaricin,griseofulvin, ciclopirox, haloprogin, tolnaftate, undecylenate, and thesecond agent is nystatin. Not wishing to be bound by theory, antifungalproperties of polyenes such as nystatin are linked to bindingergosterol. Thus, the beneficial effects of combining a polyene with oneor more antifungal agents described herein into a single treatmentcomposition have never before been realized. For example, imidazoleantifungals and polyenes are not typically combined since it is thoughtthat the presence of one (imidazole) reduces the number of binding sitesavailable for the other (polyene).

Excipient Inert Powder

The topical pastes described herein include one or more excipient inertpowders. The presence of the excipient inert powder imparts a number ofbeneficial properties with the respect to the topical pastes describedherein. The excipient inert powder reduces the active ingredientconcentrations of the anti fungal agent. Reduced concentrations ofantifungal agent are desirable for the treatment of certain patientssuch as, for example, children with diaper rash or other sensitiveindividuals. In this aspect, the concentrations of the antifungal agentare reduced to safe, but still efficacious, levels for these subjects.

Additionally, the excipient inert powder can impart sweat and/ormoisture absorption capabilities to the compositions described herein.Here, this absorption capability is believed to be beneficial because itreduces the suitability of the affected areas for further fungal growth.In still another aspect, the excipient inert powder acts as a skinlubricant to reduce the skin friction, chafing, and discomfort that arecommon to intertrigo, candidal diaper dermatitis, and other fungalinfections of the skin.

Examples of excipient inert powders useful herein include, but are notlimited to talc, starch, zinc oxide, zinc carbonate, magnesium oxide,magnesium carbonate, calamine, calcium carbonate, kaolin, titaniumdioxide, or any combination thereof. As will be discussed below, theselection and amount of excipient inert powder can vary depending uponthe application.

Pharmaceutically Acceptable Topical Carrier

The topical pastes described herein include a pharmaceuticallyacceptable topical carrier. In one aspect, the pharmaceuticallyacceptable topical carrier includes a cream, lotion, gel, or any otherpharmaceutically acceptable excipient that can be topically applied to asubject. The nature of the pharmaceutically acceptable excipient canvary depending upon the application.

In one aspect, the pharmaceutically acceptable excipient is anoil-in-water cream. Not wishing to be bound by theory, the use of anoil-in-water cream in combination with the excipient inert powderresults in the formation of a hygroscopic paste that is useful incontrolling the environment where the fungal infection is located. Bycontrolling the environment at the site of infection, the antifungalagent present in the paste is much more effective in treating and/orpreventing further re-occurring fungal infections in the subject.

Oil-in-water creams known in the art can be used in this aspect. Thetype and amount of oil or oily components present in the cream can vary.Examples of such components include, but are not limited to, mineraloil, petrolatum, parabens, or glycols (e.g., ethylene glycol). Theamount of oil or oily components can vary depending upon theenvironmental conditions as well as the amount of moisture at the siteof application in the subject. In one aspect, the amount of oilycomponent(s) can be from 10% to 50% by weight of the topical paste. Inanother aspect, the amount of oily component(s) is 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, or 50%, where any value can form a lower or upperendpoint of a range. In another aspect, the amount of water present inthe oil-in-water cream is greater than 45% by weight of the cream, 45%to 80% by weight of the cream, or 45%, 50%, 55%, 60%, 65%, 70%, 75%, or80% by weight of the cream, when any value can form a lower or upperendpoint of a range.

In one aspect, a useful oil-in-water cream is Dermabase manufactured byPaddock Laboratories, Inc., which is composed of purified water,petrolatum, mineral oil, cetostearyl alcohol, propylene glycol,isopropyl palmitate, methylparaben, and propylparaben. In anotheraspect, the oil-in-water cream is Vanicream, which is composed of water,white petrolatum, cetearyl alcohol, ceteareth-20, sorbitol solution,propylene glycol, simethicone, glyceryl monostearate, polyethyleneglycol monostearate, sorbic acid, and BHT. In another aspect, theoil-in-water cream is Velvachol manufactured by Healthpoint, LTD. whichis composed of water, petrolatum, mineral oil, acetyl alcohol, stearylalcohol, methylparaben, butylparaben, and propylparaben. In anotheraspect, a useful oil-in-water emulsion cream base is Aquaphilic®manufactured by Medco Lab Inc., which is composed of water, stearylalcohol, white petrolatum, propylene glycol, sorbitol, isopropylpalmitate, methylparaben, and propylparaben.

In another aspect, the pharmaceutically acceptable excipient is anoil-free cream base. In this embodiment, the oil-free cream does notcontain any oil components such as mineral oil, petrolatum, parabens, orglycols (e.g., ethylene glycol). In one aspect, the oil-free cream baseis VersaBase® manufactured by PCCA which is composed of water,ethylhexyl stearate, emulsifying wax, tocopherly acetatedisodium EDTA,sorbitol, cyclopentanesiloxane, methylchloroisothiazolinone andmethylisothiazolinone. In another aspect, the pharmaceuticallyacceptable excipient is a lotion. In another aspect, the lotion isVersaBase® topical lotion base. In another aspect, the pharmaceuticallyexcipient is a gel. In another aspect, the gel is VersaBase® topical gelbase.

In other aspects, the pharmaceutically acceptable excipient is not awater-in-oil base. As discussed above, the topical pastes describedherein are hygroscopic pastes that are useful in controlling theenvironment where the fungal infection is located. The pastes describedherein wick or remove moisture from the application site of the subject,thereby controlling the humidity at the site of infection. Bycontrolling the environment at the site of infection, the antifungalagent present in the paste is much more effective in treating and/orpreventing further re-occurring fungal infections in the subject.Additionally, the water-in-oil base can prevent air from contacting theinfection site, which can promote the growth of bacteria under anaerobicconditions. Thus, in certain aspects, the pharmaceutically acceptableexcipient is not a water-in-oil base, as these bases can trap waterand/or prevent the release of water at the infection site as well asprevent air circulation at the infection site, which ultimately producesan environment of sustained or increased fungal growth and infection.Additionally, water-in-oil bases are greasy and are more difficult toremove when compared to other bases (e.g., oil-in-water bases).

Preparation of Topical Pastes

The topical pastes described herein are formulated with a sufficientamount of excipient inert powder and to produce a paste. The pastesdescribed herein are semisolid materials composed of granular particlesdispersed throughout the pharmaceutically acceptable topical carrier.The primary source of the granular particles is derived from theexcipient inert powder. However, when the antifungal agent used toprepare the topical paste is also a granular material, the antifungalagent can also contribute to the formation of the topical paste. Theamount of the granular particles can also vary depending upon themoisture levels in the environment. For example, in hot, humidconditions, the higher amounts of granular particles can be included inthe composition.

In one aspect, the topical paste is produced by admixing one or moreantifungal agents and excipient inert powder in the pharmaceuticallyacceptable topical carrier so that the antifungal agent and excipientinert powder are evenly or homogeneously dispersed throughout thepharmaceutically acceptable topical carrier. Techniques known in the artfor homogeneously dispersing the ingredients of the topical paste can beused herein.

In one aspect, the topical pastes described herein are composed of 10%to 80% by weight granular particles (excipient inert powder andoptionally antifungal agent). In another aspect, the topical paste iscomposed of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, or 80% by weight granular particles, where any value can forma lower and upper end-point of a range. In another aspect, the topicalpaste is composed of 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10%to 40%, 10% to 30%, 20% to 30%, 20% to 80%, 30% to 80%, 40% to 80%, 50%to 80%, 60% to 80%, or 70% to 80% by weight granular particles.

In one aspect, the antifungal agent used to produce the paste can beadmixed with the excipient inert powder and the pharmaceuticallyacceptable topical carrier as a pure powder. Thus, in one aspect, pureantifungal compound (>99%) in powder form can be admixed with theexcipient inert powder and the pharmaceutically acceptable topicalcarrier to produce the topical paste. The following is a non-limitingexample of a 2% by weight topical paste of ketoconazole (100 g intotal):

-   2 g ketoconazole (99.987% purity)-   16 g talc-   10 g starch-   7 g zinc oxide-   5 g magnesium oxide-   60 g cream

In another aspect, the antifungal agent has been formulated into apowder prior to admixing with the excipient inert powder and thepharmaceutically acceptable topical carrier. An example of this isnystatin. Pure nystatin has not less than 4,400 units/mg (or 4,400,000units/gm). The pharmaceutical concentration of nystatin is 100,000units/gm. Therefore, the bulk of nystatin powder is an inert powder.Thus, when the antifungal has been formulated into a powder, theantifungal agent and an inert powder present in the antifungal agent canalso contribute the degree of pastiness of the topical paste.

In another aspect, topical paste produced by the process comprisingadmixing

-   a. first composition comprising an antifungal agent in a    pharmaceutically acceptable topical carrier, and-   b. an excipient inert powder,    wherein the excipient inert powder is in a sufficient amount to form    a paste comprising granular particles evenly distributed in the    pharmaceutically acceptable topical cream.

In this aspect, the antifungal agent has been formulated in thepharmaceutically acceptable topical carrier prior to the addition of theexcipient inert powder. For example, 1% clotrimazole cream (OTC) canadmixed with one or more excipient inert powders to produce a topicalpaste with varying degrees of pastiness. In one aspect, the firstcomposition is 0.5% to 1.3% clotrimazole cream, 0.5% to 2% ketoconazolecream, 0.5% to 2% miconazole cream, 0.5% to 1% oxiconazole cream, 0.5%to 1% luliconazole cream, or 0.5% to 2% terbinafine cream. In anotheraspect, the first composition is 1% clotrimazole cream, 1% clotrimazolelotion, 1% clotrimazole topical solution, 2% ketoconazole cream, 2%miconazole nitrate cream, 1% oxiconazole nitrate cream, 1% oxiconazolenitrate lotion, 1% econazole nitrate cream, 1% luliconazole cream, 1%terbinafine cream, and combinations thereof.

It will be appreciated that the actual preferred amounts of antifungalagent will vary according to the specific compound being utilized, theparticular compositions formulated, the mode of application, and theparticular sites and subject being treated. Dosages for a given host canbe determined using conventional considerations, e.g. by customarycomparison of the differential activities of the subject compounds andof a known agent, e.g., by means of an appropriate conventionalpharmacological protocol. Physicians and formulators, skilled in the artof determining doses of pharmaceutical compounds, will have no problemsdetermining dose according to standard recommendations (Physicians DeskReference, Barnhart Publishing—1999). In one aspect, the antifungalagent is from 0.25 to 5% by weight of the paste. In another aspect, theantifungal agent is from 0.25 to 5%, 0.25 to 4%, 0.25 to 3%, or 0.5 to3% by weight of the paste.

In one aspect, the topical paste is composed of

-   (1) a single antifungal agent composed of clotrimazole,    ketoconazole, miconazole, oxiconazole, econazole, nystatin,    luliconazole, terbinafine, fluconazole, voriconazole, itraconazole,    caspofungin, micafungin, naftifine, butenafine, amorolfine,    ravuconazole, posaconazole, flucytosine, sertaconazole,    efinaconazole, enilaconazole, saperconazole, sulconazole,    terconazole, tioconazole, nikkomycin Z, anidulafungin (LY303366),    pimaricin, griseofulvin, ciclopirox, haloprogin, tolnaftate, or    undecylenate;-   (2) an excipient inert powder comprising talc, starch, zinc oxide,    zinc carbonate, magnesium oxide, magnesium carbonate, calamine,    calcium carbonate, kaolin, titanium dioxide, or any combination    thereof; and-   (3) an oil-in-water cream,    wherein the paste comprises from 10% to 80% by weight granular    particles, here the source of the granular particles is the    excipient inert powder alone or in combination with the antifungal    agent.

In one aspect, the topical pastes are independently the following byweight including carrier and inert powder):

-   Clotrimazole 1%-   Ketoconazole 2%-   Miconazole 2%-   Oxiconazole 1%-   Econazole 1%-   Luliconazole 1%-   Fluconazole 1%-   Itraconazole 1%-   Voriconazole 1%-   Sertaconazole 2%-   Sulconazole 1%-   Nystatin 2.27%-   Terbinafine 1%-   Naftifine 2%-   Butenafine 1%-   Ciclopirox 0.77%-   Efinaconazole 10%

In another aspect, the paste includes two or more antifungal agents. Forexample, the antifungal agent includes a first agent and second agent,wherein the first agent is clotrimazole, ketoconazole, miconazole,oxiconazole, econazole, luliconazole, terbinafine, fluconazole,voriconazole, itraconazole, caspofungin, micafungin, naftifine,butenafine, amorolfine, ravuconazole, posaconazole, flucytosine,sertaconazole, efinaconazole, enilaconazole, saperconazole, sulconazole,terconazole, tioconazole, nikkomycin Z, anidulafungin (LY303366),pimaricin, griseofulvin, ciclopirox, haloprogin, tolnaftate,undecylenate, and the second agent is nystatin.

In the case when two or more antifungal agents are to be used, theagents can independently be used as a bulk powder and/or formulated in acarrier (e.g., cream). For example, clotrimazole cream (1%) can beformulated with nystatin powder and additional excipient inert powder toproduce the topical paste.

In one aspect, when nystatin is used as one of the antifungal agents,the nystatin (powder or cream) has an activity of 10,000 units/gram to500,000 units/gram; 50,000 units/gram to 250,000 units/gram; 75,000units/gram to 150,000 units/gram, or 100,000 units/gram. In anotheraspect, the nystatin powder is from 1% to 3% b weight of the powder andhas an a from 75,000 units/gram to 150,000 units/gram.

In one aspect, when two antifungal agents are employed, the first agentis from 0.1 to 3% by weight of the paste and nystatin is from 0.1% to 3%by weight of the paste. In another aspect, the first agent is from 0.1to 3%, 0.1 to 2%, 0.5 to 2%, or 0.5 to 1% by weight of the paste andnystatin is from 0.1 to 3%, 0.1 to 2%, 0.5 to 2%, or 0.5 to 1% by weightof the paste.

In another aspect, the topical paste is composed of 20% to 80% b weightantifungal agent (1% or 2% cream), and 20% to 80% by weight nystatinpowder (100,000 units/gram). In another aspect, the topical compositionis composed of 30% to 70%, 40% to 70%, 50% to 70%, or 60% by weightantifungal agent (1% or 2% cream), and 20% to 70%, 30% to 60%, 30% to50%, or 40% by weight nystatin powder (100,000 units/gram).

In another aspect, the topical composition is a topical paste composedof 1% clotrimazole cream and nystatin powder having an activity of100,000 units/gm, wherein the weight ratio of clotrimazole to nystatinpowder is from 0.5:1 to 5:1; 1:1 to 5:1; 1:1 to 4:1; 1:1 to 3:1; 1:1 to2:1 or about 3:2.

In one aspect, the topical composition is one of the following:

-   1. At least 50% of an antifungal cream, lotion, or solution, and at    least 25% of Nystatin Topical Powder (100,00 units/gm).-   2. Clotrimazole Cream (1%) and Nystatin Topical Powder (100,000    units/gm) in a 2:1 weight ratio.-   3. Clotrimazole Cream (1%) and Nystatin Topical Powder (100,000    units/gm) in a 3:2 weight ratio.-   4. Clotrimazole Lotion (1%) and Nystatin Powder (100,000 units/gm)    in a 3:2 weight ratio.-   5. Clotrimazole Lotion (1%) and Nystatin Topical Powder (100,000    units/gm) in a 2:1 weight ratio.-   6. Clotrimazole Topical Solution (1%) and Nystatin Topical Powder    (100,000 units/gm) in a 2:1 weight ratio.-   7. Clotrimazole Topical Solution (1%) and Nystatin Topical Powder    (100,000 units/gm) in a 3:2 weight ratio.-   8. Ketoconazole Cream (2%) and Nystatin Topical Powder (100,000    units/gm) in a 2:1 weight ratio.-   9. Ketoconazole Cream (2%) and Nystatin Topical Powder (100,000    units/gm) in a 3:2 weight ratio.-   10. Miconazole Nitrate Cream (2%) and Nystatin Topical Powder    (100,000 units/gm) in a 2:1 to 3:2 weight ratio.-   11. Oxiconazole Nitrate Cream or lotion (1%) and Nystatin Topical    Powder (100,000 units/gm) in a 2:1 to 3:2 weight ratio.-   12. Econazole Nitrate Cream (1%) and Nystatin Topical Powder    (100,000 units/gm) in a 2:1 to 3:2 weight ratio.

In one aspect, the topical paste includes less than or equal to 50% byweight of an imidazole cream, lotion, or solution (1% or 2%), less thanor equal to 40% by weight Nystatin Cream or powder (100,000 units/gm),and less than or equal to 40% inert powder, wherein the sum of thecomponents is 100%.

In one aspect, the topical paste is one of the following:

-   1. Clotrimazole Cream (1%), Nystatin Cream (100,000 units/gm), and    Corn Starch USP in a 40%/30%/30% by weight mixture.-   2. Clotrimazole Cream (1%), Nystatin Cream, (100,000 units/gm), and    Corn Starch in a 35%/30%/35% weight mixture.-   3. Clotrimazole Cream (1%), Nystatin Cream, (100,000 units/gm), and    Corn Starch in a 50%/25%/25% weight mixture.-   4. Clotrimazole Lotion (1%), Nystatin Cream (100,000 units/gm), and    Corn Starch in a 40%/25%/35% weight mixture.-   5. Clotrimazole Lotion (1%), Nystatin Cream (100,000 units/gm), and    Corn Starch in a 50%/20%/30% weight mixture.-   6. Clotrimazole Cream (1%), Nystatin Cream (100,000 units/gm), and    Talc in a 40%/30%/30% weight mixture.-   7. Clotrimazole Cream (1%), Nystatin Cream (100,000 units/gm), and    Talc in a 35%/30%/35% weight mixture.-   8. Clotrimazole Cream (1%), Nystatin Cream USP (100,000 units/gm),    and Talc in a 50%/25%/25% weight mixture.-   9. Clotrimazole Lotion USP (1%), Nystatin Cream (100,000 units/gm),    and Talc USP in a 40%/25%/35% weight mixture.-   10. Clotrimazole Lotion (1%), Nystatin Cream (100,000 units/gm), and    Talc in a 50%/20%/30% weight mixture.-   11. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 40%30%/30% weight mixture.-   12. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 35%/30%/35% weight mixture.-   13. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Corn Starch USP in a 50%/25%/25% weight mixture.-   14. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Talc in a 40%/30%/30% weight mixture.-   15. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Talc in a 35%/30%/35% weight mixture.-   16. Miconazole Nitrate Cream (2%), Nystatin Cream (100,000    units/gm), and Talc in a 50%/25%/25% weight mixture.-   17. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 40%/30%/30% weight mixture.-   18. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 35%/30%/35% weight mixture.-   19. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 50%/25%/25% weight mixture.-   20. Oxiconazole Nitrate Lotion (1%), Nystatin Cream (100,000    units/gm), and Corn Starch in a 40%/25%/35% weight mixture.-   21. Oxiconazole Nitrate Lotion (1%), Nystatin Cream (100,000    units/gm), and Corn Starch USP in a 50%/20%/30% weight mixture.-   22. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm), and Talc in a 40%/30%/30% weight mixture.-   23. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm) and Talc in a 35%/30%/35% weight mixture.-   24. Oxiconazole Nitrate Cream (1%), Nystatin Cream (100,000    units/gm), and Talc in a 50%/25%/25% weight mixture.-   25. Oxiconazole Nitrate Lotion (1%), Nystatin Cream (100,000    units/gm), and Talc in a 40%/25%/35% weight mixture.-   26. Oxiconazole Nitrate Lotion (1%), Nystatin Cream, 100,000    units/gm, and Talc in a 50%/20%/60% weight mixture.

Any of the topical pastes described herein can include one or moreadditional components that can provided additional benefits in additionto the enhanced antifungal properties imparted by the paste. Forexample, the pastes described herein can include an antipruitic agent tostop or prevent itching, an analgesic, an antiseptic agent, or anycombination thereof. In one aspect, any of the topical pastes describedherein can include menthol in the amount of 1% to 3% by weight of thepaste, phenol in the amount of 1% to 2.8% by weight of the paste,camphor in the amount of 1% to 5% by weight of the paste, or anycombination thereof.

II. Methods of Use

The topical pastes described herein can be used in a variety ofapplications related to the treatment of fungal infections. A method fortreating a fungal infection includes contacting an area showing symptomsof a fungal infection with the compositions defined above. The pastesdescribed herein are superior alternatives to conventional treatmentsconsisting of anti fungal creams, ointments, or solutions, and/orantifungal/steroid combination creams or ointments. Additionally, incertain aspects, the combination of two antifungal agents as in thepastes described herein will be able to effectively eliminate or reducethe growth of strains resistant to one, but not both, activeingredients. Thus, the pastes described herein possess significantadvantages over conventional treatments when dealing with complicatedcases and/or simultaneous infections by multiple strains of fungi.

In one aspect, the fungi causing the infection are yeasts such as, forexample, Candida albicans or other Candida spp. including C. glabrata,C. rugosa, C. parapsilosis, C. tropicalis, or C. dubliniensis In anotheraspect, the fungi are dermatophytes such as, for example, Trichophytonspp. and Microsporum spp. In a further aspect, the dermatophytes areEpidermophyton floccosum, T. rubrum, T. interdigitale, T. tonsurans, T.violaceum, T. concentricum, T. schoenleinii, T. soudanense, T.mentagrophytes, T. equinum, T. erinacei, T. verrucosum, M. audouinii, M.ferragineum, M. canis, M. gypseum, M. nanum, and/or M. cookei.

In another aspect, the fungal infection causes a fungal disease such as,for example, tinea cruris, tinea corporis, tinea versicolor,candidiasis, tinea pedis, intertrigo, seborrhoeic dermatitis, diaperrash, tinea capitis, tinea barbae, thrush, diaper dermatitis (childrenand adults) or a combination thereof. In a still further aspect, thefungal disease causes symptoms such as, for example, itching, a burningsensation, flaking skin, peeling skin, rash, redness, cracking skin,scaly skin, blisters, macerated skin, odor, or a combination thereof.

In one aspect, the pastes described herein are useful in treating orpreventing intertrigo. Intertrigo is an inflammation or rash caused byovergrowth of yeast species such as, for example, Candida albicans.Intertrigo afflicts areas of the body that have skin touching skin suchas the groin, armpits, between the buttocks, under heavy breasts, in theinner thighs, beneath penile foreskin, the perianal area, genital area,between the toes, in the crease of the neck, and abdominal fat foldsprovide the perfect environment for Candida albicans imbalance andsymptom presentation. The body heat and moisture present in theseintertriginous areas provide a prime milieu for the proliferation ofyeasts such as Candida, leading to irritation, redness, intense itching,burning, pain and odor. Maceration and/or characteristic satellitereddened plaques/lesions often present under the breast, in theabdominal folds, and in the inguinal area. Intertrigo frequentlypresents as candidal diaper rash as well.

Factors that frequently cause or contribute to intertrigo include immunedeficiencies, obesity, diabetes, incontinence, heat, humid weather,tight or abrasive clothing or underclothing, lack of air circulation,friction between skin folds, excessive sweating and moisture, poorhygiene, malnutrition, inadequate bra support, inflammatory skinconditions like psoriasis in skin folds, and the use of topicalsteroids. Infants and toddlers, with their chubbiness, shorter necks,and bended posture, are also at increased risk for intertrigo.

Intertrigo is also particularly common among immunocompromised patients.“Immunocompromised patients” are individuals with weakened immunesystems resulting from, for example, HIV or AIDS, chemotherapy and/orradiation such as for cancer treatment, long-term corticosteroid orglucocorticoid therapy, anti-rejection drugs taken by transplantrecipients, cancers of the bone marrow or the blood, splenectomy, orcongenital deficiencies.

In another aspect, the pastes described herein are useful in treating orpreventing candidal diaper rash. Candidal diaper dermatitis (i.e.,diaper rash) is a common yeast overgrowth infection caused by Candidaalbicans that frequently presents in the perianal area and between thebuttocks of infants and toddlers. Visits to outpatient pediatric officesfor diaper dermatitis total 1 million per year. Infant skin is thinnerthan that of adults, produces fewer secretions, and is more susceptibleto irritation and infection. Measures to decrease maceration of the skinin these areas include frequent diaper changes, avoiding imperviousdiaper covers, and long periods without diapers. Still, topicalantifungal therapy is necessary for resolution of candidal diaper rash.

The pastes described herein can be used to treat fungal infections anddiseases and also so to reduce the severity of or eliminate symptomscaused by fungal infections and diseases. In one aspect, a method fortreating a fungal disease in a subject is provided. In this aspect, asubject is contacted with an effective amount of one or more of theantifungal compositions described herein. In a further aspect, thesubject is a mammal. In a still further aspect, the mammal is a human orother primate, a cat, a dog, cattle, a horse, a pig, a sheep, a goat, amouse, a rabbit, a rat, a guinea pig, or any other domesticated,captive, or livestock mammal.

In a further aspect, the method involves contacting the affected area(s)of a subject with the compositions described herein. This contact mayoccur one, two, three, or four times daily. In one aspect, the topicalcompositions described herein can be applied to an area that issusceptible to fungal infection. In this aspect, the topicalcompositions described herein can prevent infection by the fungus.

In another aspect, the method involves initiating treatment at the onsetof symptoms associated with fungal infection or disease. In anotheraspect, the method involves initiating treatment at any time after theonset of symptoms associated with fungal infection or disease. In oneaspect, treatment is stopped upon resolution of the symptoms associatedwith fungal infection or disease. In another aspect, treatment iscontinued after the resolution of the symptoms. In this aspect,continued treatment is believed to help prevent the recurrence ofsymptoms and/or the resurgence of resistant fungal strains. In stillanother aspect, treatment may be continued for 1, 2, 3, 4, 5, 6, or upto 7 days after the resolution of symptoms. In yet another aspect, thecompositions may be applied sparingly or liberally to the affected area.In some aspects, the affected area is washed with water or a mild soapprior to application of the compositions described herein.

In a still further aspect, the methods and compositions described hereinspecifically exclude topical and/or systemic treatment withglucocorticoids. Thus, the compositions and mixtures disclosed hereincan aid in the restoration of natural flora balance and skin foldintegrity without the use of glucocorticoids.

In the alternative, a glucocorticoid compound and the compositionsdescribed herein can be simultaneously administered. In another aspect,the compositions described herein can include other active antifungalingredients or other ingredients that provide immediate relief fromsymptoms associated with fungal infection and disease.

In one aspect, the area to be treated is first pretreated prior toapplication of the topical compositions described herein. For example,the area of the subject can be first contacted with Burow's solution,either topically or included as part of a cold compress, prior toapplication of the compositions described herein. In this aspect,Burow's solution cleanses the affected area and/or allows the subjectimmediate relief from symptoms such as itching, burning, and the like.Prior to application of the topical application, the area to be treatedshould be dried as thoroughly as possible, as moisture can promotefungal growth on the skin.

In other aspects, the topical pastes described herein can beincorporated into articles that can be used to treat or prevent fungalinfections. For example, the pastes can be incorporated in or applied todiapers and surgical pads where fungal infections are prevalent. Here,the articles can help reduce or control moisture at the site ofinfection or potential infection and ultimately treat or prevent fungalinfection.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, and methods described and claimed herein aremade and evaluated, and are intended to be purely exemplary and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers (e.g., amounts, temperature, etc.) but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C. or is at ambienttemperature, and pressure is at or near atmospheric. There are numerousvariations and combinations of reaction conditions, e.g., componentconcentrations, desired solvents, solvent mixtures, temperatures,pressures and other reaction ranges and conditions that can be used tooptimize the product purity and yield obtained from the describedprocess. Only reasonable and routine experimentation will be required tooptimize such process conditions.

Trial 1

An obese female with severe chemotherapy-related inguinal intertrigo wastreated and observed. Initially, one-dimensional therapy withclotrimazole cream 1% applied 3 times a day neutralized progressionwithin 4 days, but she remained uncomfortably symptomatic and tissuesremained red and still macerated in part due to continued sweating inthe infected area.

Nystatin-Triamcinolone cream was instituted on day 5 due to unrelentingitching, burning, and inflammation in the groin. Symptomatic relieffollowed within 2 days and applications of the antifungal-steroid creamcombination continued for 10 days with substantial symptomatic andapparent therapeutic resolution. However, recurrence and escalationresumed a week later following this apparent resolution.

Aware of the possible risks associated with prolonged steroid use, thefollowing antifungal agents were singularly employed: ketoconazole cream2% was applied 2 to 3 times a day with significant yet marginal lastingefficacy, and discontinuation after 8 days was followed with miconazolecream 2% applied 2 to 3 times a day for more than 7 days. Antimicrobialtherapy was discontinued and Baby Powder (talc) was applied twice a day,which appeared to enable integumentary improvement in a dry,chemical-free environment; redness, inflammation, and maceration abatedsignificantly.

Nystatin powder was then “tested” near onset of the next recurrence;bathing or cleansing and drying of affected and surrounding tissuespreceded application two or three times a day. Substantial improvementensued initially and appeared to provide a more sustainable healing“environment”, though intertrigo presented repeatedly from time to time.

Paste dosage formulations of the present invention were subsequentlyevaluated. Although several creamy paste dosage formulations describedherein were efficacious, the female subject responded best to a creamypasty clotrimazole cream/nystatin powder formulation (a mixture of 20grams of nystatin powder spatulated into 30 grams of clotrimazolecream). Higher degrees of pastiness were employed in increasinglyelevated situation with correspondingly favorable results. Variousclinical presentations observed over time suggested ratios ranging from4:1 to 1:1 cream to powder. Resolution lasting months was achieved inthe inguinal and upper thigh regions as well as occasional flare-upsunder heavy breasts. Repeated yet far less frequent challenges overseveral years yielded consistent, superior and reliable results. Thecycle of recalcitrance and frequent resurgence has remained resolved inthis subject for the past 3 years.

Trial 2

A second obese, elderly female subject experienced similar favorable andlasting results using a creamy paste dosage formulations (20 grams ofnystatin powder spatulated into 30 grams of clotrimazole cream)described herein following decades of frequent intertrigo treatment withconventional single-entity antifungal creams or powders andantifungal/steroid combinations. This subject also continues to rely onswift, predictable, and lasting resolution from occasional flare-ups.

Trial 3

A third male subject who experienced occasional intertrigo over severalyears was evaluated. Nystatin-triamcinolone cream was initiallyprescribed and applied twice daily on the infected areas. Althoughsignificant relief from intense itching and burning was achieved within3 days followed by a 90% reduction in inflammatory presentation within 2weeks, reoccurrence ensued a week later with heat and exercise-inducedsweating as aggravating factors. Once again, nystatin-triamcinolonecream reduced symptoms within a few days, and nystatin cream was appliedtwice a day for 3 more weeks but total resolution would not occur.

Other antimicrobial creams including miconazole nitrate, clotrimazole,and ketoconazole were intermittently applied in successive flare-upsituations over the next 4 months; however, lasting resolution appearedunachievable as this cycle of recalcitrant yeast overgrowth refused torespond and abate with conventional pharmaceuticals.

Next, several topical herb formulas containing various blends ofcalendula, tea tree oil, chamomile, echinacea, ginger, coconut oil,rosemary, organic jatoba, olive oil, thyme, vitamin E, lavender, andother pure essential oils were evaluated. Mixtures of these componentswere also evaluated in order to maximize efficacy of the formulations.On several occasions, oral coconut oil capsules and iodine tablets wereemployed without fasting impact or predictable efficacy. Topicallavender and tea tree oil formulations held the most utility but provedfar too caustic when applied to macerated intertriginous regions. Mostothers simply lacked therapeutic benefit. Ultimately, none proved worthyof mention or recommendation from a pharmacist recognized as one whoonly endorses superior products in any category.

Conventional pharmaceutical antifungals were revisited, this time incombination. Cream/cream, ointment/ointment, solution/cream,lotion/cream mixtures of the various azoles/nystatin were employedseeking enhanced efficacy and potential expanded coverage; disappointinglack of synergism was the result.

Finally, comprehensive intertrigo management beginning with applicationof a mixture of 20 grams of nystatin powder spatulated into 30 grams ofclotrimazole cream interrupted the prolonged cycle of partial remissionfollowed by recurrence, escalation, and recalcitrance. Varying degreesof pastiness were subsequently employed depending on degree ofmaceration, heat, and moisture presence. Affected and surrounding areaswere cleansed and dried thoroughly prior to liberal application up to 4times a day. Twice daily application proved sufficient after 4 days, andonce daily maintenance with a creamier mixture after 10 days carriedtherapy to term on day 15. Ancillary measures employed at various stagesof treatment included occasional and soothing burows solution astringentcompresses and frequent underwear changes.

In the 5 years since, occasional flare-ups of inguinal and perinealintertrigo have occurred from time to time allowing opportunities forfurther validation of the utility of the formulation described above;congruent with previous findings, higher degrees of pastiness wereemployed in increasingly elevated moisture situations withcorrespondingly favorable results. Incredibly, microbial balance andskin fold healing is often restored within 3 days when treatment isinitiated in a timely fashion. Though most complicated clinicalpresentations require 10 to 14 days, total microbial eradication andoverkill is unnecessary when follow up measures to control heat andmoisture are employed following symptom resolution and integumentarynormalcy restoration.

For the sake of ongoing study, challenge, and comparison, the subjectwas administered a 1:1 mixture of clotrimazole cream and nystatin creamto treat inguinal intertrigo that had spread to the scrotum. However,this formulation provided limited results when compared to theadministration of the 3:2 clotrimazole cream/nystatin powder paste,which was applied within 4 days with accelerated results consistent withabove.

Disappointing and discouraging fungicidal activity observations becamepredictably remarkable remedy with paste formulation and application ofthe same active pharmaceutical ingredient(s) (API(s)) employedpreviously. Unlike the pastes that controlled site moisture as well asyeast overgrowth, current azole creams, solutions, lotions, and nystatincream or ointment products, by themselves or in combination wereunremarkable and lacked potential efficacy in simple and complicatedyeast overgrowth presentations. The pastes described herein remained themost encouraging object of present and future product study anddevelopment from a bulk active or a combination of API's; increasinglyadsorbent pastes are appropriate with increasingly elevated moisturepresence.

Lastly, a paste dosage foam of the allylamine anti fungal terbinafinerecently demonstrated enhanced efficacy in the remedy of heat relatedinguinal and buttocks intertrigo in the subject of Trial 3.

In summary, the paste formulations described herein are superioralternatives to current and standard singular antifungals andantifungal/steroid combinations in the treatment of intertrigo incomplicated patient situations as well as prompt flare-up resolution ofCandidal diaper dermatitis, which permits the resumption of bathercreams/ordinary protectants applied prophylactically.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the compounds, compositions, and methods described herein.

Various modifications and variations can be made to the compounds,compositions and methods described herein. Other aspects of thecompounds, compositions and methods described herein will be apparentfrom consideration of the specification and practice of the compounds,compositions and methods disclosed herein. It is intended that thespecification and examples be considered as exemplary.

What is claimed:
 1. A topical paste consisting of a. an antifungal agentselected from the group consisting of terbinafine or terbinafinehydrochloride, b. an excipient inert powder, and c. a pharmaceuticallyacceptable topical carrier selected from the group consisting of anoil-in-water cream or oil-free water-based cream, wherein the paste iscomposed of from 10% to 80% by weight granular particles, wherein thesource of the granular particles is the excipient inert powder alone orin combination with the antifungal agent.
 2. The paste of claim 1,wherein the antifungal agent is from 0.25 to 5% by weight of the paste.3. The paste of claim 1, wherein the antifungal agent is from 0.5 to 3%by weight of the paste.
 4. The paste of claim 1, wherein the excipientinert powder comprises talc, starch, zinc oxide, zinc carbonate,magnesium oxide, magnesium carbonate, calamine, calcium carbonate,kaolin, titanium dioxide, or any combination thereof.
 5. The paste ofclaim 1, wherein the pharmaceutically acceptable topical carrier is anoil-in-water cream.
 6. The paste of claim 1, wherein thepharmaceutically acceptable topical carrier is an oil-free water-basedcream.
 7. A method for treating or preventing a fungal disease, themethod comprising applying the paste of claim 1 to the subject, whereinthe fungal disease comprises tinea cruris, tinea corporis, tineaversicolor, candidiasis, tinea pedis, intertrigo, seborrheic dermatitis,diaper rash, tinea capitis, tinea barbae, thrush, diaper dermatitis, ora combination thereof.
 8. The method of claim 7, wherein the fungaldisease is intertrigo.
 9. The method of claim 7, wherein the fungaldisease is diaper rash.
 10. The method of claim 7, wherein thecomposition treats at least one symptom comprising itching, a burningsensation, flaking skin, peeling skin, rash, redness, cracking skin,scaly skin, blisters, macerated skin, odor, or a combination thereof.11. The method of claim 7, wherein the subject has a weakened immunesystem resulting from HIV, AIDS, chemotherapy or radiation.
 12. Thepaste of claim 1, wherein the antifungal agent is terbinafinehydrochloride.
 13. The paste of claim 1, wherein the antifungal agent isfrom 0.25 wt % to 1 wt % of the paste.
 14. The paste of claim 1, whereinthe antifungal agent is terbinafine hydrochloride in the amount of from0.25 wt % to 1 wt % of the paste.
 15. The paste of claim 5, whereinoil-in-water cream comprises a mixture of water, petrolatum, mineraloil, cetostearyl alcohol, propylene glycol, isopropyl palmitate,methylparaben, and propylparaben.
 16. The paste of claim 6, whereinoil-free water-based cream comprises a mixture of water, ethylhexylstearate, emulsifying wax, tocopheryl acetate, disodium EDTA, sorbitol,cyclopentanesiloxane, methylchloroisothiazolinone andmethylisothiazolinone.
 17. The paste of claim 1, wherein the paste iscomposed of 10% to 50% by weight granular particles, where the source ofthe granular particles is the excipient inert powder alone or incombination with terbinafine or terbinafine hydrochloride.
 18. The pasteof claim 1, wherein the pharmaceutically acceptable topical carrier isan oil-in-water cream having water in the amount of 45% to 80% by weightof the cream.